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Review
. 2024 Sep 23;6(1):vdae162.
doi: 10.1093/noajnl/vdae162. eCollection 2024 Jan-Dec.

Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation

Laura Huhtala  1 , Goktug Karabiyik  1 , Kirsi J Rautajoki  1
Affiliations
Review

Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation

Laura Huhtala et al. Neurooncol Adv. .

Abstract

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants. The only characteristic, recurrent genetic aberration of AT/RTs is biallelic inactivation of SMARCB1 (or SMARCA4). These genes are members of the mSWI/SNF chromatin-remodeling complex, which regulates various developmental processes, including neural differentiation. This review explores AT/RT subgroups regarding their distinct SMARCB1 loss-of-function mechanisms, molecular features, and patient characteristics. Additionally, it addresses the ongoing debate about the oncogenic relevance of cell-of-origin, examining the influence of developmental stage and lineage commitment of the seeding cell on tumor malignancy and other characteristics. Epigenetic dysregulation, particularly through the regulation of histone modifications and DNA hypermethylation, has been shown to play an integral role in AT/RTs' malignancy and differentiation blockage, maintaining cells in a poorly differentiated state via the insufficient activation of differentiation-related genes. Here, the differentiation blockage and its contribution to malignancy are also explored in a cellular context. Understanding these mechanisms and AT/RT heterogeneity is crucial for therapeutic improvements against AT/RTs.

Keywords: INI1; cell differentiation; cell-of-origin; epigenetic regulation; pediatric tumor.

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Conflict of interest statement

None declared.

Figures

Figure 1.
Figure 1.
mSWI/SNF has a multitude of regulatory functions during neural cell differentiation, related to the dynamic switches in its subcomposition. Different subcompositions of mSWI/SNF are indicated with various colors. Colors are not indicative of classification into canonical, non-canonical, and pBAF. (A) During the early stages of embryonic development, mSWI/SNF is essential for pluripotency maintenance and self-renewal. mSWI/SNF increases the expression of key pluripotency genes NANOG, SOX2, and OCT4 and stabilizes STAT3 binding to its target regions. (B) In neural stem cells, mSWI/SNF functions to maintain self-renewal and suppresses premature cell differentiation. A certain subcomposition of mSWI/SNF interacts with REST (an important repressor of neuronal differentiation) and enhances its binding to PAX6 target sites, leading to their suppression. During this developmental phase, mSWI/SNF suppresses the SHH-pathway and enhances Notch signaling, which further inhibits neuronal differentiation. Moreover, mSWI/SNF represses the expression of OLIG2 to prevent premature oligodendrocyte development. (C) The switch in mSWI/SNF subcomposition acts as a trigger for neuronal differentiation. During the developmental process, the expression of different mSWI/SNF subunits undergoes changes. It has been proposed that the interaction between REST and mSWI/SNF is lost, while the interaction between mSWI/SNF and PAX6 persists, promoting the expression of PAX6 targets.,, (D) mSWI/SNF promotes neuronal maturation. mSWI/SNF subcomposition, specific to post-mitotic neurons, interacts with ASCL1 (an important driver of neuronal differentiation). This interaction is seemingly independent of the ASCL1 pioneer factor function. In addition, neuronal mSWI/SNF is required for CREST to bind to its target sites and promote dendritic outgrowth. (E) mSWI/SNF may function to promote neural crest (NC) lineage commitment and migration. In NC cells, mSWI/SNF, in collaboration with CHD7, activates NC cell-specific genes to promote cell type-specific expression. (F) mSWI/SNF may function to regulate gliogenesis. Loss of mSWI/SNF interaction with PAX6 or the loss of specific subunits leads to premature gliogenesis. Furthermore, the interaction of mSWI/SNF with REST seems vital for inducing gliogenesis, but the exact mechanisms remain unclear.,,, (G) mSWI/SNF may function to promote oligodendrocyte lineage commitment. OLIG2 may target mSWI/SNF to specific genomic regions to initiate oligodendrocyte differentiation. Created in BioRender. Huhtala, L. (2024) BioRender.com/d75m420.
Figure 2.
Figure 2.
SMARCB1 inactivation leads to the development of different AT/RT subgroups depending on the phase of cell development. The neural cell differentiation window during which SMARCB1 inactivation leads to AT/RT development spans from neural stem cells to neural progenitor cells. During other stages of differentiation, SMARCB1 loss is lethal (before the neural stem cell phase) or does not similarly affect cell differentiation (more mature cells). The cell of origin for SMARCA4 inactivated tumors is still unclear due to the shortage of data. Nonetheless, different AT/RT subgroups are likely to arise from different developmental phases, which contributes to their epigenetic and transcriptomic characteristics, but more research is needed to conclusively determine the cells of origin in each subgroup. Created in BioRender. Huhtala, L. (2024) BioRender.com/u10p943.
Figure 3.
Figure 3.
Molecular and clinical characteristics of AT/RT subgroups. AT/RTs are classified into 4 distinct subgroups: AT/RT-MYC, AT/RT-TYR, AT/RT-SHH, and AT/RT-SMARCA4, the 3 first of which are more extensively characterized. These subgroups exhibit diverse characteristics in terms of location, age, and sex distribution. Loss of SMARCB1 function, as a hallmark of AT/RTs, differs between subgroups (while loss of SMARCA4 is observed on AT/RT-SMARCA4 instead). Furthermore, each subgroup is associated with distinct pathway enrichments, although some genes, such as EZH2, SUZ12, EED, AURKA, and HDAC1/2, are commonly upregulated across major AT/RT subgroups. Immune infiltration levels vary among subgroups, with AT/RT-SHH exhibiting the lowest levels of immune infiltration. Furthermore, recent studies have identified subgroup-specific therapeutic vulnerabilities, providing potential targets for new treatment strategies. Created in BioRender. Rautajoki, K. (2024) BioRender.com/t07a339.
Figure 4.
Figure 4.
Mechanisms of suppressed neural differentiation in SMARCB1 deficient AT/RT and the key genes and transcription factors known to exhibit dysregulation. Both deregulated histone modifications and DNA hypermethylation affect the differentiation blockage observed in AT/RTs. The re-expression of SMARCB1 in AT/RT cells leads to H3K27 acetylation, detachment of the ncBAF complex from the chromatin, and cell cycle arrest. While many efforts have been made to overcome the disease, the inhibitors, including DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors as well as inhibitors against BRD9, EZH2, Notch pathway, and tyrosine kinases (TK), have shown promising and partly subgroup-specific efficacy in AT/RT. Created in BioRender. Rautajoki, K. (2024) BioRender.com/g54p437.
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